Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-substituted-hydrazinecarbothioamides
Identifieur interne : 000298 ( Pmc/Corpus ); précédent : 000297; suivant : 000299Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-substituted-hydrazinecarbothioamides
Auteurs : Subhas S. Karki ; Amol A. Kulkarni ; Sujeet Kumar ; Suresh Kumar Veliyath ; Erik De Clercq ; Jan BalzariniSource :
- Medicinal Chemistry Research [ 1054-2523 ] ; 2012.
Abstract
Various 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (
Derivative
Url:
DOI: 10.1007/s00044-012-0184-x
PubMed: NONE
PubMed Central: 7079969
Links to Exploration step
PMC:7079969Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-substituted-hydrazinecarbothioamides</title><author><name sortKey="Karki, Subhas S" sort="Karki, Subhas S" uniqKey="Karki S" first="Subhas S." last="Karki">Subhas S. Karki</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Kulkarni, Amol A" sort="Kulkarni, Amol A" uniqKey="Kulkarni A" first="Amol A." last="Kulkarni">Amol A. Kulkarni</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Kumar, Sujeet" sort="Kumar, Sujeet" uniqKey="Kumar S" first="Sujeet" last="Kumar">Sujeet Kumar</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Veliyath, Suresh Kumar" sort="Veliyath, Suresh Kumar" uniqKey="Veliyath S" first="Suresh Kumar" last="Veliyath">Suresh Kumar Veliyath</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.5596.f</institution-id><institution-id institution-id-type="ISNI">0000000106687884</institution-id><institution>Rega Institute for Medical Research,</institution><institution>KU Leuven,</institution></institution-wrap>Minderbroedersstraat 10, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.5596.f</institution-id><institution-id institution-id-type="ISNI">0000000106687884</institution-id><institution>Rega Institute for Medical Research,</institution><institution>KU Leuven,</institution></institution-wrap>Minderbroedersstraat 10, 3000 Leuven, Belgium</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7079969</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079969</idno><idno type="RBID">PMC:7079969</idno><idno type="doi">10.1007/s00044-012-0184-x</idno><idno type="pmid">NONE</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000298</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000298</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-substituted-hydrazinecarbothioamides</title><author><name sortKey="Karki, Subhas S" sort="Karki, Subhas S" uniqKey="Karki S" first="Subhas S." last="Karki">Subhas S. Karki</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Kulkarni, Amol A" sort="Kulkarni, Amol A" uniqKey="Kulkarni A" first="Amol A." last="Kulkarni">Amol A. Kulkarni</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Kumar, Sujeet" sort="Kumar, Sujeet" uniqKey="Kumar S" first="Sujeet" last="Kumar">Sujeet Kumar</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="Veliyath, Suresh Kumar" sort="Veliyath, Suresh Kumar" uniqKey="Veliyath S" first="Suresh Kumar" last="Veliyath">Suresh Kumar Veliyath</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</nlm:aff></affiliation></author><author><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.5596.f</institution-id><institution-id institution-id-type="ISNI">0000000106687884</institution-id><institution>Rega Institute for Medical Research,</institution><institution>KU Leuven,</institution></institution-wrap>Minderbroedersstraat 10, 3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.5596.f</institution-id><institution-id institution-id-type="ISNI">0000000106687884</institution-id><institution>Rega Institute for Medical Research,</institution><institution>KU Leuven,</institution></institution-wrap>Minderbroedersstraat 10, 3000 Leuven, Belgium</nlm:aff></affiliation></author></analytic><series><title level="j">Medicinal Chemistry Research</title><idno type="ISSN">1054-2523</idno><idno type="eISSN">1554-8120</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Abstract</title><p>Various 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (<bold>4a</bold>, <bold>b</bold>) and 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(phenyl-4-substituted)hydrazinecarbothioamide (<bold>5a</bold>–<bold>h</bold>) derivatives were synthesized. The compounds were screened for cytotoxicity against human HeLa and CEM T-lymphocytes as well as murine L1210 cells. The compounds were also screened for β-lactamase inhibitory activity, antiviral, antibacterial, and antifungal activity against various strains of microorganisms. Several of these compounds were endowed with low micromolar 50 %-cytostatic concentration (IC<sub>50</sub>) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells (L1210) were also the most inhibitory against human T-lymphocyte (CEM) tumor cells. Derivative 2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(4-methoxyphenyl)hydrazinecarbothioamide <bold>5c</bold> emerged as the most potent cytostatic compound among the tested compounds. Derivatives <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> showed antiviral activity against HEL cell cultures (IC<sub>50</sub> 11–20 μM). Moderate antimicrobial activity was observed for all derivatives. The encouraging cytostatic and antiviral activity data provide an adequate rationale for further modification of these molecular scaffolds.</p></sec><sec><title>Graphical abstract</title><p>Derivative <bold>5c</bold> (1.9–4.4 μM) emerged as the most potent cytostatic compound among the tested compounds. Derivatives <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> showed antiviral activity against HEL cell cultures (IC<sub>50</sub> 11–20 μM). <graphic position="anchor" xlink:href="44_2012_184_Figa_HTML" id="MO1"></graphic></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Andreani, A" uniqKey="Andreani A">A Andreani</name></author><author><name sortKey="Bellini, S" uniqKey="Bellini S">S Bellini</name></author><author><name sortKey="Burnelli, S" uniqKey="Burnelli S">S Burnelli</name></author><author><name sortKey="Granaiola, M" uniqKey="Granaiola M">M Granaiola</name></author><author><name sortKey="Leoni, A" uniqKey="Leoni A">A Leoni</name></author><author><name sortKey="Locatelli, A" uniqKey="Locatelli A">A Locatelli</name></author><author><name sortKey="Morigi, R" uniqKey="Morigi R">R Morigi</name></author><author><name sortKey="Rambaldi, M" uniqKey="Rambaldi M">M Rambaldi</name></author><author><name 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Singh</name></author><author><name sortKey="Stables, Jp" uniqKey="Stables J">JP Stables</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xiao, Z" uniqKey="Xiao Z">Z Xiao</name></author><author><name sortKey="Hao, Y" uniqKey="Hao Y">Y Hao</name></author><author><name sortKey="Liu, B" uniqKey="Liu B">B Liu</name></author><author><name sortKey="Qian, L" uniqKey="Qian L">L Qian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, W" uniqKey="Zhang W">W Zhang</name></author><author><name sortKey="Go, Ml" uniqKey="Go M">ML Go</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Med Chem Res</journal-id><journal-id journal-id-type="iso-abbrev">Med Chem Res</journal-id><journal-title-group><journal-title>Medicinal Chemistry Research</journal-title></journal-title-group><issn pub-type="ppub">1054-2523</issn><issn pub-type="epub">1554-8120</issn><publisher><publisher-name>Springer-Verlag</publisher-name><publisher-loc>New York</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7079969</article-id><article-id pub-id-type="publisher-id">184</article-id><article-id pub-id-type="doi">10.1007/s00044-012-0184-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject></subj-group></article-categories><title-group><article-title>Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-substituted-hydrazinecarbothioamides</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Karki</surname><given-names>Subhas S.</given-names></name><address><phone>+91-80-23325611</phone><fax>+91-80-23425373</fax><email>subhasskarki@gmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kulkarni</surname><given-names>Amol A.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kumar</surname><given-names>Sujeet</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Veliyath</surname><given-names>Suresh Kumar</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>De Clercq</surname><given-names>Erik</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Balzarini</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.411053.2</institution-id><institution-id institution-id-type="ISNI">0000 0001 1889 7360</institution-id><institution>Department of Pharmaceutical Chemistry,</institution><institution>KLE University’s College of Pharmacy,</institution></institution-wrap>Rajajinagar, Bangalore, 560010 Karnataka India</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.5596.f</institution-id><institution-id institution-id-type="ISNI">0000000106687884</institution-id><institution>Rega Institute for Medical Research,</institution><institution>KU Leuven,</institution></institution-wrap>Minderbroedersstraat 10, 3000 Leuven, Belgium</aff></contrib-group><pub-date pub-type="epub"><day>26</day><month>8</month><year>2012</year></pub-date><pub-date pub-type="ppub"><year>2013</year></pub-date><volume>22</volume><issue>4</issue><fpage>2014</fpage><lpage>2022</lpage><history><date date-type="received"><day>11</day><month>4</month><year>2012</year></date><date date-type="accepted"><day>25</day><month>7</month><year>2012</year></date></history><permissions><copyright-statement>© Springer Science+Business Media, LLC 2012</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract id="Abs1"><sec><title>Abstract</title><p>Various 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (<bold>4a</bold>, <bold>b</bold>) and 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(phenyl-4-substituted)hydrazinecarbothioamide (<bold>5a</bold>–<bold>h</bold>) derivatives were synthesized. The compounds were screened for cytotoxicity against human HeLa and CEM T-lymphocytes as well as murine L1210 cells. The compounds were also screened for β-lactamase inhibitory activity, antiviral, antibacterial, and antifungal activity against various strains of microorganisms. Several of these compounds were endowed with low micromolar 50 %-cytostatic concentration (IC<sub>50</sub>) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells (L1210) were also the most inhibitory against human T-lymphocyte (CEM) tumor cells. Derivative 2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(4-methoxyphenyl)hydrazinecarbothioamide <bold>5c</bold> emerged as the most potent cytostatic compound among the tested compounds. Derivatives <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> showed antiviral activity against HEL cell cultures (IC<sub>50</sub> 11–20 μM). Moderate antimicrobial activity was observed for all derivatives. The encouraging cytostatic and antiviral activity data provide an adequate rationale for further modification of these molecular scaffolds.</p></sec><sec><title>Graphical abstract</title><p>Derivative <bold>5c</bold> (1.9–4.4 μM) emerged as the most potent cytostatic compound among the tested compounds. Derivatives <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> showed antiviral activity against HEL cell cultures (IC<sub>50</sub> 11–20 μM). <graphic position="anchor" xlink:href="44_2012_184_Figa_HTML" id="MO1"></graphic></p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>2,3-Dioxo-2,3-dihydroindole</kwd><kwd>Thiosemicarbazones</kwd><kwd>Cytotoxicity assay</kwd><kwd>Antiviral activity</kwd><kwd>Antimicrobial activity</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer Science+Business Media New York 2013</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p>Isatin has been known for about 150 years and has recently been found, like 2,3-dioxo-indoles and endogenous polyfunctional heterocyclic compounds, to exhibit biological activity in mammals (Somogyi, <xref ref-type="bibr" rid="CR19">2001</xref>). Schiff bases and Mannich bases of isatin are known to possess a wide range of pharmacological properties including antibacterial (Pandeya <italic>et al.,</italic><xref ref-type="bibr" rid="CR11">1998</xref>; Sarangapani and Reddy, <xref ref-type="bibr" rid="CR16">1994</xref>; Varma and Nobles, <xref ref-type="bibr" rid="CR23">1975</xref>), anticonvulsant (Sridhar <italic>et al.,</italic><xref ref-type="bibr" rid="CR20">2002</xref>; Varma <italic>et al.,</italic><xref ref-type="bibr" rid="CR24">2004</xref>), anti-HIV (Pandeya <italic>et al.,</italic><xref ref-type="bibr" rid="CR11">1998</xref>, <xref ref-type="bibr" rid="CR12">1999a</xref>, <xref ref-type="bibr" rid="CR13">b</xref>, <xref ref-type="bibr" rid="CR14">2000</xref>; Sriram <italic>et al.,</italic><xref ref-type="bibr" rid="CR21">2000</xref>), antifungal (Pandeya <italic>et al.,</italic><xref ref-type="bibr" rid="CR12">1999a</xref>, <xref ref-type="bibr" rid="CR13">b</xref>), antiviral (Singh <italic>et al.,</italic><xref ref-type="bibr" rid="CR18">1983</xref>), and anticancer activity (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Karki <italic>et al.,</italic><xref ref-type="bibr" rid="CR4">2004</xref>, <xref ref-type="bibr" rid="CR5">2007</xref>, <xref ref-type="bibr" rid="CR6">2009</xref>). A variety of 3-substituted indolin-2-ones have been utilized as anticancer drugs or drug candidates (Mologni <italic>et al.,</italic><xref ref-type="bibr" rid="CR10">2010</xref>, Beauchard <italic>et al.,</italic><xref ref-type="bibr" rid="CR3">2009</xref>, Zhang and Go <xref ref-type="bibr" rid="CR26">2009</xref>, Andreani <italic>et al.,</italic><xref ref-type="bibr" rid="CR1">2010</xref>). A representative member of this class is sunitinib [SU11248, Sutent™; Pfizer, Inc.] which is currently used in the clinics as a multi-targeting tyrosine kinase inhibitor with antiangiogenic activity (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Sun <italic>et al.,</italic><xref ref-type="bibr" rid="CR22">2003</xref>). 6-Methoxycarbonyl group-substituted indolin-2-ones [BIBF1000, BIBF1120] are potent inhibitors of VEGFR-1/2/3, PDGFRa, and FGFR-1, with low cross-reactivity against a panel of other kinases (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Roth <italic>et al.,</italic><xref ref-type="bibr" rid="CR15">2009</xref>). While BIBF1120 is currently being evaluated in phase III clinical trials in the treatment of non-small cell lung cancer and is in clinical development for other tumor types. Indirubin was identified as the active ingredient of a traditional Chinese recipe [Danggui Longhui Wan] that was used for the treatment of chronic myelogenous leukemia (CML) (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Xiao <italic>et al.,</italic><xref ref-type="bibr" rid="CR25">2002</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>Structures of indolin-2-ones</p></caption><graphic xlink:href="44_2012_184_Fig1_HTML" id="MO2"></graphic></fig></p><p>Thiosemicarbazones of various aldehydes and ketones occupy a special place among organic ligands, since they contain various donor atoms and are able to change density depending on the starting reagents and their reaction conditions. Isatin-3-thiosemicarbazones (1<italic>H</italic>-indole-2,3-dioxo-3-thiosemicarbazones) have been studied extensively due to their important biological activities (Karki <italic>et al.,</italic><xref ref-type="bibr" rid="CR6">2009</xref>), since 1-methylisatin-3-thiosemicarbazone (Marboran) was found to be active in the treatment of smallpox. Previous studies by our group have revealed the promising cytotoxic, and anticonvulsant properties of various 2,3-dioxo-2,3-dihydroindole thiosemicarbazones (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) (Karki <italic>et al.,</italic><xref ref-type="bibr" rid="CR6">2009</xref>). Therefore, we have performed the synthesis of new <italic>N</italic>-4-aryl thiosemicarbazone derivatives of substituted 2,3-dioxo-2,3-dihydroindoles and evaluated them for cytotoxic, antiviral, and antimicrobial activity.</p></sec><sec id="Sec2"><title>Results and discussion</title><sec id="Sec3"><title>Chemistry</title><p>The compounds in series <bold>4</bold> and <bold>5</bold> were prepared by the methodologies outlined in Scheme <xref rid="Sch1" ref-type="fig">1</xref>. The synthesis of 1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione derivatives (<bold>3</bold>) was carried out by mannich base reaction of 2,3-dioxy-2,3-dihydroindoles or 5-chloro-2,3-dioxy-2,3-dihydroindoles (<bold>2</bold>) with diethylamine in the presence of formaldehyde. The synthesis of <italic>N</italic>-diethylaminomethyl-2-oxo-1,2-dihydroindole hydrazinecarbothioamides (<bold>4a</bold>, <bold>b</bold>, <bold>5a</bold>–<bold>h</bold>) was carried out by reacting 1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione derivatives (<bold>3</bold>) with thiosemicarbazide and <italic>N</italic><sup>4</sup>-aryl thiosemicarbazides under reflux in ethanol in the presence of catalytic amounts of glacial acetic acid. <sup>1</sup>H-NMR spectroscopy indicated that the compounds exist as single isomers in solution.<fig id="Sch1"><label>Scheme 1</label><caption><p>The reagents used were as follows: <italic>i</italic> CCl<sub>3</sub>CH(OH)<sub>2</sub>/H<sub>2</sub>SO<sub>4</sub>/Na<sub>2</sub>SO<sub>4</sub>; <italic>R</italic><sub>1</sub>=H, Cl, <italic>ii</italic> (C<sub>2</sub>H<sub>5</sub>)NH/HCHO, <italic>iii</italic> NH<sub>2</sub>C(S)NHNH<sub>2</sub>, <italic>iv</italic><italic>R</italic><sub>2</sub>C<sub>6</sub>H<sub>4</sub>NHC(S)NHNH<sub>2</sub>. The nature of the <italic>R</italic><sub>1</sub> and <italic>R</italic><sub>2</sub> substituent are presented in Table <xref rid="Tab1" ref-type="table">1</xref></p></caption><graphic xlink:href="44_2012_184_Sch1_HTML" id="MO3"></graphic></fig></p></sec><sec id="Sec4"><title>Biological activity</title><p>All of the compounds were assayed for cytotoxicity against human HeLa and CEM T-lymphocytes as well as murine L1210 cells. These data are summarized in Table <xref rid="Tab1" ref-type="table">1</xref>. Compound <bold>5c</bold> was the most cytostatic among all compounds evaluated against the tumor cell lines (IC<sub>50</sub> in the low micromolar range (1.9–4.4 μM)).<table-wrap id="Tab1"><label>Table 1</label><caption><p>Results of cytotoxicity in murine L1210 cells, human HeLa, and CEM T-lymphocytes, and β-lactamase inhibitory activity</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2">Compound</th><th align="left" rowspan="2"><italic>R</italic><sub>1</sub></th><th align="left" rowspan="2"><italic>R</italic><sub>2</sub></th><th align="left" colspan="3">IC<sub>50</sub><sup>a</sup> (μM)</th><th align="left" rowspan="2">Time for decolorization of I<sub>2</sub> (s)</th><th align="left" rowspan="2">Activity (u ml<sup>−1</sup>)</th><th align="left" rowspan="2">Inactivation (%)</th></tr><tr><th align="left">L1210</th><th align="left">CEM</th><th align="left">HeLa</th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">H</td><td align="left">–</td><td align="left">121 ± 35</td><td align="left">164 ± 21</td><td align="left">123 ± 85</td><td char="." align="char">128.6</td><td char="." align="char">46.7</td><td char="." align="char">38.2</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">Cl</td><td align="left">–</td><td align="left">148 ± 15</td><td align="left">71 ± 7</td><td align="left">44 ± 22</td><td char="." align="char">121.5</td><td char="." align="char">49.4</td><td char="." align="char">34.6</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">H</td><td align="left">H</td><td align="left">13 ± 3</td><td align="left">11 ± 0</td><td align="left">8.3 ± 0.0</td><td char="." align="char">159.5</td><td char="." align="char">37.6</td><td char="." align="char">50.2</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">H</td><td align="left">Cl</td><td align="left">11 ± 1</td><td align="left">10 ± 1</td><td align="left">7.6 ± 0.9</td><td char="." align="char">129.7</td><td char="." align="char">46.3</td><td char="." align="char">38.7</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">H</td><td align="left">OCH<sub>3</sub></td><td align="left">2.4 ± 0.0</td><td align="left">1.9 ± 0.9</td><td align="left">4.4 ± 2.4</td><td char="." align="char">123.6</td><td char="." align="char">48.5</td><td char="." align="char">35.7</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">H</td><td align="left">CH<sub>3</sub></td><td align="left">29 ± 3</td><td align="left">12 ± 0</td><td align="left">12 ± 0</td><td char="." align="char">145.8</td><td char="." align="char">41.2</td><td char="." align="char">45.5</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">Cl</td><td align="left">H</td><td align="left">49 ± 2</td><td align="left">40 ± 3</td><td align="left">34 ± 0</td><td char="." align="char">156.3</td><td char="." align="char">38.4</td><td char="." align="char">49.2</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">Cl</td><td align="left">Cl</td><td align="left">>125</td><td align="left">>125</td><td align="left">>125</td><td char="." align="char">142.3</td><td char="." align="char">42.2</td><td char="." align="char">44.2</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">Cl</td><td align="left">OCH<sub>3</sub></td><td align="left">11 ± 2</td><td align="left">6.9 ± 4.3</td><td align="left">9.2 ± 0.9</td><td char="." align="char">167.9</td><td char="." align="char">35.7</td><td char="." align="char">52.6</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">Cl</td><td align="left">CH<sub>3</sub></td><td align="left">9.5 ± 0.5</td><td align="left">4.6 ± 4.0</td><td align="left">8.6 ± 0.3</td><td char="." align="char">120.6</td><td char="." align="char">49.8</td><td char="." align="char">34.1</td></tr><tr><td align="left">Melphalan</td><td align="left">–</td><td align="left"><bold>–</bold></td><td align="left">3.2 ± 0.6</td><td align="left">2.2 ± 0.2</td><td align="left">2.1 ± 0.02</td><td char="." align="char">–</td><td char="." align="char">–</td><td char="." align="char">–</td></tr><tr><td align="left">Control</td><td align="left">–</td><td align="left"><bold>–</bold></td><td align="left">–</td><td align="left"><bold>–</bold></td><td align="left">–</td><td char="." align="char">79.5</td><td char="." align="char">75.5</td><td char="." align="char">–</td></tr><tr><td align="left">Potassium clavulanate</td><td align="left">–</td><td align="left"><bold>–</bold></td><td align="left">–</td><td align="left"><bold>–</bold></td><td align="left">–</td><td char="." align="char">240.50</td><td char="." align="char">25.0</td><td char="." align="char">67.0</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>IC<sub>50</sub> concentrations of compounds required to inhibit the growth of the tumor cells by 50 %</p></table-wrap-foot></table-wrap></p><p>The most potent inhibitor of murine L1210 cell proliferation (<bold>5c</bold>) was also the most inhibitory to human T-lymphocyte (CEM) and HeLa cell proliferation. The introduction of <italic>R</italic><sub>2</sub>-benzyl substitution in the thiosemicarbazone derivative of series <bold>5</bold> often led to more potent inhibitors of tumor cell proliferation (<bold>5a</bold>–<bold>h</bold>). Replacement of the hydrogen by chlorine atom did not improve the potentiation of the cytostatic activity (compare <bold>5a</bold> with <bold>5b</bold>) (Table <xref rid="Tab1" ref-type="table">1</xref>). Whereas, replacement of the chlorine atom at <italic>R</italic><sub>2</sub> by a methoxy group often resulted in a marked (equal) potentiation of cytostatic activity (<bold>5b</bold> with <bold>5c</bold>).</p><p>Replacement of hydrogen atom at <italic>R</italic><sub>1</sub> by chlorine atom did not yield any improvement in potency (compare <bold>5a</bold>, <bold>5b</bold> and <bold>5d</bold> with <bold>5e</bold>–<bold>h</bold>). Replacing hydrogen atom at <italic>R</italic><sub>1</sub> and <italic>R</italic><sub>2</sub> by chlorine resulted in a complete loss of activity (<bold>5f</bold>). By keeping chlorine atom at <italic>R</italic><sub>1</sub> and CH<sub>3</sub> and OCH<sub>3</sub> at <italic>R</italic><sub>2</sub>, resulted in slight improvement of cytostatic activity (<bold>5g</bold> and <bold>5h</bold>).</p><p>The antiviral screening of <bold>4a</bold>, <bold>b</bold> and <bold>5a</bold>–<bold>h</bold> was performed using an MTS-based CPE reduction assay (Kumar <italic>et al.,</italic><xref ref-type="bibr" rid="CR7">2010</xref>) against feline corona virus (FIPV) and feline herpes virus in CRFK cell culture; herpes simplex virus-1 (KOS) (HSV-1 KOS), herpes simplex virus-2 (G) (HSV-2G), vaccinia virus (VV), vesicular stomatitis virus (VSV), and herpes simplex virus-1 TK KOS ACV<sup>r</sup> (HSV-1 TK KOS ACV<sup>r</sup>) in HEL cell cultures; VSV, Coxsackie virus B4 (CV-B4), and respiratory syncytial virus (RSV) in HeLa cell cultures; influenza A virus H1N1 subtype, influenza A virus H3N2 subtype, and influenza B virus in MDCK cell cultures; parainfluenza-3 virus (PI-3V), reovirus-1 (RV-1), Sindbis virus (SV), CV-B4, and Punta Toro virus (PTV) in Vero cell cultures.</p><p>Compounds <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> exhibited moderate antiviral activity in HEL cells in comparison to standard compounds. No specific antiviral effects were noted for any of the compounds in CRFK, MDCK, or Vero cell cultures (Tables <xref rid="Tab2" ref-type="table">2</xref>, <xref rid="Tab3" ref-type="table">3</xref>, <xref rid="Tab4" ref-type="table">4</xref>, <xref rid="Tab5" ref-type="table">5</xref>, <xref rid="Tab6" ref-type="table">6</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Results of anti-FIPV and anti-feline herpes virus activity and cytotoxicity in CRFK cell cultures</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2">Compound</th><th align="left" rowspan="2">CC<sub>50</sub><sup>a</sup> (μM)</th><th align="left" colspan="2">EC<sub>50</sub><sup>b</sup> (μM)</th></tr><tr><th align="left">FIPV</th><th align="left">Feline herpes virus</th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">73.8</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">32.3</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">4.0</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">3.5</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">3.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">6.9</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">9.1</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">3.6</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">17.5</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left">HHA (μg ml<sup>−1</sup>)</td><td align="left">>100</td><td align="left">19.5</td><td align="left">1.8</td></tr><tr><td align="left">UDA (μg ml<sup>−1</sup>)</td><td align="left">>100</td><td align="left">9.1</td><td align="left">2.4</td></tr><tr><td align="left">Ganciclovir</td><td align="left">>100</td><td align="left">>100</td><td align="left">7.3</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>50 % cytotoxic concentration</p><p><sup>b</sup>50 % effective concentration, determined by colorimetric formazan-based MTS assay</p></table-wrap-foot></table-wrap><table-wrap id="Tab3"><label>Table 3</label><caption><p>Results of cytotoxicity and antiviral activity of compounds in HEL cell cultures</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2">Compound</th><th align="left" rowspan="2">Minimum cytotoxic concentration<sup>a</sup> (μM)</th><th align="left" colspan="5">EC<sub>50</sub><sup>b</sup> (μM)</th></tr><tr><th align="left">HSV-1 (KOS)</th><th align="left">HSV-2 (G)</th><th align="left">VV</th><th align="left">VSV</th><th align="left">HSV-1 TK<sup>−</sup> KOS ACV<sup>r</sup></th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">20</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">>100</td><td align="left">20</td><td align="left">15</td><td align="left">20</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">100</td><td align="left">15</td><td align="left">15</td><td align="left">≥20</td><td align="left">>20</td><td align="left">≥20</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">100</td><td align="left">14</td><td align="left">12</td><td align="left">11</td><td align="left">>20</td><td align="left">≥20</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left">Brivudin</td><td align="left">>250</td><td align="left">0.08</td><td align="left">150</td><td align="left">29</td><td align="left">>250</td><td align="left">>250</td></tr><tr><td align="left">Cidofovir</td><td align="left">>250</td><td align="left">5</td><td align="left">1.5</td><td align="left">10</td><td align="left">>250</td><td align="left">6</td></tr><tr><td align="left">Acyclovir</td><td align="left">>250</td><td align="left">1.0</td><td align="left">0.7</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td></tr><tr><td align="left">Ganciclovir</td><td align="left">>100</td><td align="left">0.09</td><td align="left">0.07</td><td align="left">>100</td><td align="left">>100</td><td align="left">≥20</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>Required to cause a microscopically detectable alteration of normal cell morphology</p><p><sup>b</sup>Required to reduce virus-induced cytopathogenicity by 50 %</p></table-wrap-foot></table-wrap><table-wrap id="Tab4"><label>Table 4</label><caption><p>Results of cytotoxicity and antiviral activity of compounds in HeLa cell cultures</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="3">Compound</th><th align="left" colspan="2">Cytotoxicity (μM)</th><th align="left" colspan="6">EC<sub>50</sub><sup>b</sup> (μM)</th></tr><tr><th align="left" rowspan="2">CC<sub>50</sub><sup>a</sup></th><th align="left" rowspan="2">Minimum cytotoxic concentration<sup>b</sup></th><th align="left" colspan="2">VSV</th><th align="left" colspan="2">CV-B4</th><th align="left" colspan="2">RSV</th></tr><tr><th align="left">Visual CPE score</th><th align="left">MTS</th><th align="left">Visual CPE score</th><th align="left">MTS</th><th align="left">Visual CPE score</th><th align="left">MTS</th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">10.8</td><td align="left">≥20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">9.8</td><td align="left">≥4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">>100</td><td align="left">≥4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">10.7</td><td align="left">≥20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">13.5</td><td align="left">≥20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">9.4</td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">13.2</td><td align="left">4</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">>100</td><td align="left">≥4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left">DS-5000<sup>c</sup></td><td align="left">>100</td><td align="left">>100</td><td align="left">20</td><td align="left">14.8</td><td align="left">>100</td><td align="left">>100</td><td align="left">4</td><td align="left">2.8</td></tr><tr><td align="left">(<underline>S</underline>)-DHPA</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td></tr><tr><td align="left">Ribavirin</td><td align="left">>250</td><td align="left">>250</td><td align="left">50</td><td align="left">12.1</td><td align="left">50</td><td align="left">28.5</td><td align="left">10</td><td align="left">4.6</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>50 % cytotoxic concentration</p><p><sup>b</sup>Minimum compound concentration that causes a microscopically detectable alteration of normal cell morphology</p><p><sup>c</sup>50 % effective concentration, as determined by a colorimetric formazan-based MTS assay. Data in μg ml<sup>−1</sup></p></table-wrap-foot></table-wrap><table-wrap id="Tab5"><label>Table 5</label><caption><p>Results of cytotoxicity and antiviral activity of compounds in Vero cell cultures</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2">Compound</th><th align="left" rowspan="2">Minimum cytotoxic concentration<sup>a</sup> (μM)</th><th align="left" colspan="5">EC<sub>50</sub><sup>b</sup> (μM)</th></tr><tr><th align="left">PI-3V</th><th align="left">RV-1</th><th align="left">SV</th><th align="left">CV-B4</th><th align="left">PTV</th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">20</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">4</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">4</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">≥4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td><td align="left">>4</td></tr><tr><td align="left">DS-5000<sup>c</sup></td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">20</td><td align="left">100</td><td align="left">100</td></tr><tr><td align="left">(<underline>S</underline>)-DHPA</td><td align="left">>250</td><td align="left">250</td><td align="left">250</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td></tr><tr><td align="left">Ribavirin</td><td align="left">>250</td><td align="left">50</td><td align="left">>250</td><td align="left">>250</td><td align="left">>250</td><td align="left">112</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>Required to cause a microscopically detectable alteration of normal cell morphology</p><p><sup>b</sup>Required to reduce virus-induced cytopathogenicity by 50 %</p><p><sup>c</sup>Data in μg ml<sup>−1</sup></p></table-wrap-foot></table-wrap><table-wrap id="Tab6"><label>Table 6</label><caption><p>Results of anti-influenza virus activity and cytotoxicity in MDCK cell cultures</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="3">Compound</th><th align="left" colspan="2">Cytotoxicity (μM)</th><th align="left" colspan="6">Antiviral EC<sub>50</sub><sup>c</sup> (μM)</th></tr><tr><th align="left" rowspan="2">CC<sub>50</sub><sup>a</sup></th><th align="left" rowspan="2">Minimum cytotoxic concentration<sup>b</sup></th><th align="left" colspan="2">Influenza A<break></break>H1N1 subtype</th><th align="left" colspan="2">Influenza A<break></break>H3N2 subtype</th><th align="left" colspan="2">Influenza B</th></tr><tr><th align="left">Visual CPE score</th><th align="left">MTS</th><th align="left">Visual CPE score</th><th align="left">MTS</th><th align="left">Visual CPE score</th><th align="left">MTS</th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">85.8</td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">78.3</td><td align="left">100</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td><td align="left">>20</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">1.6</td><td align="left">0.8</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">0.4</td><td align="left">0.8</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">9.2</td><td align="left">4</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">0.2</td><td align="left">0.8</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td><td align="left">>0.16</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">3.0</td><td align="left">≥0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">2.4</td><td align="left">≥0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">11.1</td><td align="left">≥0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">11.3</td><td align="left">4</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td><td align="left">>0.8</td></tr><tr><td align="left">Oseltamivir carboxylate</td><td align="left">>100</td><td align="left">>100</td><td align="left">45</td><td align="left">39.1</td><td align="left">4</td><td align="left">5.7</td><td align="left">45</td><td align="left">21.8</td></tr><tr><td align="left">Ribavirin</td><td align="left">>100</td><td align="left">≥100</td><td align="left">9</td><td align="left">11.5</td><td align="left">9</td><td align="left">6.8</td><td align="left">9</td><td align="left">8.4</td></tr><tr><td align="left">Amantadine</td><td align="left">>500</td><td align="left">>500</td><td align="left">45</td><td align="left">65.5</td><td align="left">2</td><td align="left">1.5</td><td align="left">>500</td><td align="left">>500</td></tr><tr><td align="left">Rimantadine</td><td align="left">258.9</td><td align="left">500</td><td align="left">9</td><td align="left">24.2</td><td align="left">0.1</td><td align="left">0.08</td><td align="left">>100</td><td align="left">>100</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>50 % cytotoxic concentration, as determined by colorimetric formazan-based MTS assay</p><p><sup>b</sup>Minimum compound concentration that causes a microscopically detectable alteration of normal cell morphology</p><p><sup>c</sup>50 % effective concentration, as determined by colorimetric formazan-based MTS assay</p></table-wrap-foot></table-wrap></p><p>All the synthesized compounds were screened for β-lactamase inhibitory activity and results are shown in Table <xref rid="Tab1" ref-type="table">1</xref>. Compounds namely <bold>5a</bold> and <bold>5g</bold> were capable of inactivating β-lactamase activity, and for other compounds activity was moderate in comparing to standard potassium clavulanate. Titled compounds were also screened for antibacterial activity against <italic>S. aureus, B. subtilis, K. pneumoniae, E. coli, P. vulgaris, and S. typhi</italic> and antifungal activity against <italic>A. niger and C. albicans</italic> and exhibited moderate antimicrobial activity (Table <xref rid="Tab7" ref-type="table">7</xref>).<table-wrap id="Tab7"><label>Table 7</label><caption><p>Zone of Inhibition in mm (using 50 μg ml<sup>−1</sup> as test solution)</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2">Compound</th><th align="left" colspan="6">Antibacterial activity</th><th align="left" colspan="2">Antifungal activity</th></tr><tr><th align="left"><italic>S. aureus</italic></th><th align="left"><italic>B. subtilis</italic></th><th align="left"><italic>K. pneumoniae</italic></th><th align="left"><italic>E. coli</italic></th><th align="left"><italic>P. vulgaris</italic></th><th align="left"><italic>S. typhi</italic></th><th align="left"><italic>A. niger</italic></th><th align="left"><italic>C. albicans</italic></th></tr></thead><tbody><tr><td align="left"><bold>4a</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>4b</bold></td><td align="left">+++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>5a</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td><td align="left">+++</td><td align="left">+++</td><td align="left">+++</td></tr><tr><td align="left"><bold>5b</bold></td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>5c</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>5d</bold></td><td align="left">+++</td><td align="left">+++</td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>5e</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td></tr><tr><td align="left"><bold>5f</bold></td><td align="left">+++</td><td align="left">+++</td><td align="left">++</td><td align="left">+++</td><td align="left">+++</td><td align="left">+++</td><td align="left">+++</td><td align="left">+++</td></tr><tr><td align="left"><bold>5g</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left"><bold>5h</bold></td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">+++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td><td align="left">++</td></tr><tr><td align="left">Ofloxacin</td><td align="left">++++</td><td align="left">++++</td><td align="left">++++</td><td align="left">++++</td><td align="left">++++</td><td align="left">++++</td><td align="left">–</td><td align="left">–</td></tr><tr><td align="left">Fluconazole</td><td align="left">–</td><td align="left">–</td><td align="left">–</td><td align="left">–</td><td align="left">–</td><td align="left">–</td><td align="left">++++</td><td align="left">++++</td></tr><tr><td align="left">Control</td><td align="left">+</td><td align="left">+</td><td align="left">+</td><td align="left">+</td><td align="left">+</td><td align="left">+</td><td align="left">+</td><td align="left">+</td></tr></tbody></table><table-wrap-foot><p>++++ (31–36), +++ (21–30), ++ (11–20), + (8–10) in mm</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec5"><title>Experimental</title><sec id="Sec6"><title>Chemistry</title><p>All reagents were obtained from Sigma-Aldrich, Mumbai, and Loba Chemie, Mumbai. All the solvents used in these studies were dried and distilled before use. Melting points (Mp): Veego VMP-PM digital melting point apparatus, and are uncorrected. TLC: solvent benzene:ethanol (8:2). UV spectra: Shimadzu Pharmspec 1700, UV–Vis spectrophotometer. IR spectra: Shimadzu 8400 S, FT-IR. <sup>1</sup>H-NMR spectra: 300 MHz JEOL NMR Spectrophotometer in CDCl<sub>3</sub> and DMSO-d<sub>6</sub>. Mass spectra: GCMS QP 5050 Shimadzu. All spectra were obtained from Pune University, Maharashtra, India.</p><sec id="Sec7"><title>Syntheses of the intermediate 2,3-dioxy-2,3-dihydroindoles</title><p>The synthesis of the intermediate 2,3-dioxo-2,3-dihydroindoles was accomplished using a literature methodology (Marvel and Heirs, <xref ref-type="bibr" rid="CR9">1941</xref>) and a previously reported procedure was used to convert these compounds to the corresponding 1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione. The <italic>N</italic><sup>4</sup>-arylthiosemicarbazides required for the preparation of <bold>4a</bold>, <bold>b</bold> and <bold>5a</bold>–<bold>h</bold> was prepared by a literature methodology (Sen and Sengupta, <xref ref-type="bibr" rid="CR17">1962</xref>; Lieber <italic>et al.,</italic><xref ref-type="bibr" rid="CR8">1957</xref>).</p></sec><sec id="Sec8"><title>General procedure for syntheses of <bold>4a</bold>, <bold>b</bold></title><p>A mixture of the 1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione or 5-chloro-1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione (0.005 mol), thiosemicarbazides (0.005 mol), acetic acid (0.5–1.0 ml), and ethanol (100 ml) was heated under reflux until the reaction was completed (~4 h). Approximately half of the ethanol was removed in vacuo and the solution was left overnight at room temperature. The precipitated solid was collected, washed with cold ethanol, and recrystallized from ethanol:chloroform (9:1) to give the following compounds.</p><sec id="Sec9"><title>2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (<bold>4a</bold>)</title><p>% Yield: 83, m.p.: 134–136 °C; IR (KBr) (cm<sup>−1</sup>): 1131 (C=S), 1307 (C–N), 1696 (C=O), 3005 (C–H), 3143 (NH), 3238, 3256 (NH<sub>2</sub>); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 7.0–7.7 (m, 4H, Ar–H), 9.53 (s, 2H, NH<sub>2</sub>), 11.18 (s, 1H, NH); calc. for C<sub>14</sub>H<sub>19</sub>N<sub>5</sub>OS: C-55.06, H-6.27 and N-22.93, found C-55.18, H-6.15 and N-22.69.</p></sec><sec id="Sec10"><title>2-(5-chloro-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (<bold>4b</bold>)</title><p>% Yield: 64, m.p.: 214–216 °C; IR (KBr) (cm<sup>−1</sup>): 1127 (C=S), 1305 (C–N), 1698 (C=O), 3008 (C–H), 3136 (NH), 3227, 3246 (NH<sub>2</sub>); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 7.0–7.7 (m, 3H, Ar–H), 9.53 (s, 2H, NH<sub>2</sub>), 11.18 (s, 1H, NH); calc. for C<sub>14</sub>H<sub>18</sub>ClN<sub>5</sub>OS: C-49.48, H-5.34 and N-20.61, found C-49.34, H-5.21 and N-20.69.</p></sec></sec><sec id="Sec11"><title>General procedure for syntheses of <bold>5a</bold>–<bold>h</bold></title><p>A mixture of the 1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione or 5-chloro-1-[(diethylamino)methyl]-1<italic>H</italic>-indole-2,3-dione (0.005 mol), <italic>N</italic><sup>4</sup>-aryl thiosemicarbazides (0.005 mol), acetic acid (0.5–1.0 ml), and ethanol (100 ml) was heated under reflux until the reaction was completed (approximately 4 h). Approximately half of the ethanol was removed in vacuo and the solution was left overnight at room temperature. The precipitated solid was collected, washed with cold ethanol, and recrystallized from ethanol:chloroform (9:1) to give the following compounds.</p><sec id="Sec12"><title>2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-phenylhydrazinecarbothioamide (<bold>5a</bold>)</title><p>% Yield: 69, m.p.: 230–232 °C; IR (KBr) (cm<sup>−1</sup>): 1127 (C=S), 1304 (C–N), 1713 (C=O), 3008 (C–H), 3143, 3217 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.9–7.7 (m, 9H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>20</sub>H<sub>23</sub>N<sub>5</sub>OS: C-62.97, H-6.08 and N-18.36, found C-62.53, H-5.87 and N-18.15.</p></sec><sec id="Sec13"><title><italic>N</italic>-(4-chlorophenyl)-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazine carbothioamide (<bold>5b</bold>)</title><p>% Yield: 74, m.p.: 151–153 °C; IR (KBr) (cm<sup>−1</sup>): 1129 (C=S), 1317 (C–N), 1716 (C=O), 3006 (C–H), 3128, 3209 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.4–7.7 (m, 8H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>20</sub>H<sub>22</sub>ClN<sub>5</sub>OS: C-57.75, H-5.33 and N-16.84, found C-57.39, H-5.26 and N-16.53.</p></sec><sec id="Sec14"><title>2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(4-methoxyphenyl)hydrazinecarbothioamide (<bold>5c</bold>)</title><p>% Yield: 77, m.p.: 177–179 °C; IR (KBr) (cm<sup>−1</sup>): 1119 (C=S), 1325 (C–N), 1706 (C=O), 3008 (C–H), 3120, 3202 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 3.75 (s, 3H, O–CH<sub>3</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.3–7.7 (m, 8H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>21</sub>H<sub>25</sub>N<sub>5</sub>O<sub>2</sub>S: C-61.29, H-6.12 and N-17.02, found C-61.09, H-6.09 and N-16.80.</p></sec><sec id="Sec15"><title>2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-<italic>p</italic>-tolylhydrazinecarbothioamide (<bold>5d</bold>)</title><p>% Yield: 67, m.p.: 191–193 °C; IR (KBr) (cm<sup>−1</sup>): 1125 (C=S), 1297 (C–N), 1706 (C=O), 3008 (C–H), 3135, 3219 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.32 (s, 3H, CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.3–7.7 (m, 9H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>21</sub>H<sub>25</sub>N<sub>5</sub>OS: C-63.77, H-6.37 and N-17.71, found C-63.42, H-6.14 and N-17.39.</p></sec><sec id="Sec16"><title>2-(5-chloro-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-phenylhydrazinecarbothioamide (<bold>5e</bold>)</title><p>% Yield: 72, m.p.: 181–183 °C; IR (KBr) (cm<sup>−1</sup>): 1125 (C=S), 1315 (C–N), 1718 (C=O), 3008 (C–H), 3123, 3219 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.9–7.7 (m, 8H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>20</sub>H<sub>22</sub>ClN<sub>5</sub>OS: C-57.75, H-5.33 and N-16.84, found C-57.51, H-5.37 and N-16.27.</p></sec><sec id="Sec17"><title>2-(5-chloro-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(4-chlorophenyl)hydrazinecarbothioamide (<bold>5f</bold>)</title><p>% Yield: 79, m.p.: 219–221 °C; IR (KBr) (cm<sup>−1</sup>): 1114 (C=S), 1310 (C–N), 1713 (C=O), 3007 (C–H), 3123, 3216 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.4–7.6 (m, 8H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>20</sub>H<sub>21</sub>Cl<sub>2</sub>N<sub>5</sub>OS: C-53.34, H-4.70 and N-15.55, found C-53.29, H-4.54 and N-15.28.</p></sec><sec id="Sec18"><title>2-(5-chloro-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-(4-methoxyphenyl)hydrazinecarbothioamide (<bold>5g</bold>)</title><p>% Yield: 73, m.p.: 165–167 °C; IR (KBr) (cm<sup>−1</sup>): 1123 (C=S), 1329 (C–N), 1716 (C=O), 3008 (C–H), 3127, 3224 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 3.75 (s, 3H, O–CH<sub>3</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.3–7.7 (m, 7H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>21</sub>H<sub>24</sub>ClN<sub>5</sub>O<sub>2</sub>S: C-56.56, H-5.42 and N-15.70, found C-56.26, H-5.32 and N-15.47.</p></sec><sec id="Sec19"><title>2-(5-chloro-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-<italic>N</italic>-<italic>p</italic>-tolylhydrazinecarbothioamide (<bold>5h</bold>)</title><p>% Yield: 72, m.p.: 178–180 °C; IR (KBr) (cm<sup>−1</sup>): 1128 (C=S), 1309 (C–N), 1711 (C=O), 3008 (C–H), 3125, 3228 (NH); <sup>1</sup>H-NMR (CDCl<sub>3</sub>) δ (ppm): 1.0 (t, 6H, 2CH<sub>3</sub>), 2.32 (s, 3H, CH<sub>3</sub>), 2.4 (q, 4H, 2CH<sub>2</sub>), 4.03 (s, 2H, N–CH<sub>2</sub>), 6.3–7.7 (m, 8H, Ar–H), 11.29 (s, 1H, N–NH), 11.52 (s, 1H, NH); calc. for C<sub>21</sub>H<sub>24</sub>ClN<sub>5</sub>OS: C-58.66, H-5.63 and N-16.29, found C-58.43, H-5.38 and N-16.31.</p></sec></sec></sec><sec id="Sec20"><title>Cytotoxicity assays</title><p>The methodology for undertaking the HeLa, CEM, and L1210 assays has been published previously (Baraldi <italic>et al.,</italic><xref ref-type="bibr" rid="CR2">2004</xref>). In brief, varying concentrations of the compounds were incubated at 37 °C for 72 h (HeLa and CEM T-lymphocytes) or 48 h (L1210 cells) in 200-μl 96-well-microtiter plates, and the viable tumor cell number was counted at the end of the incubation period using a Coulter Counter (Coulter Electronics, Harpenden Hertz, U.K.).</p><sec id="Sec21"><title>Antiviral assay</title><p>The antiviral screening of <bold>4a</bold>, <bold>b</bold> and <bold>5a</bold>–<bold>h</bold> was performed against FIPV and feline herpes virus in CRFK cell culture; HSV-1 KOS, HSV-2G, VV, VSV, and HSV-1 TK KOS ACVr in HEL cell cultures; VSV, CVB4, and RSV in HeLa cell cultures; PI-3V, RV-1, SV, CV-B4, and PTV in Vero cell cultures; influenza A virus H1N1 subtype, influenza A virus H3N2 subtype, and influenza B virus in MDCK cell cultures and the results are expressed as the 50 % effective concentration (EC<sub>50</sub>). Cells, grown to confluency in 96-well plates, were infected with 100 CCID<sub>50</sub> of virus, one CCID<sub>50</sub> being the 50 % cell culture infective dose. At the time of virus infection, serial dilutions of the compounds were added. The cultures were incubated at 37 °C for 3 days, until complete CPE was observed in the infected and untreated virus control.</p></sec><sec id="Sec22"><title>Cytotoxicity assay</title><p>The cytotoxicity of the compounds was evaluated in parallel with their antiviral activity in uninfected cells, and is expressed as the minimum cytotoxic concentration to cause a microscopically detectable alteration of normal cell morphology (HEL, HeLa, CRFK, MDCK, and Vero cells).</p></sec><sec id="Sec23"><title>Antiproliferative assays</title><p>The cytostatic effects of the test compounds on murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and human cervix carcinoma cells (HeLa) were evaluated as follows: an appropriate number of cells suspended in growth medium were allowed to proliferate in 200-μl wells of 96-well-microtiter plates in the presence of variable amounts of test compounds at 37 °C in a humidified CO<sub>2</sub>-controlled atmosphere. After 48 h (L1210), 72 h (CEM), or 96 h (HeLa), the number of cells was counted in a Coulter counter. The IC<sub>50</sub> value was defined as the compound concentration required to inhibit cell proliferation by 50 %.</p></sec><sec id="Sec24"><title>β-lactamase inhibitory assay</title><p>All reagents were equilibrated to 30 °C in a water bath before adding them to the reaction tubes (20 × 150 mm. Pyrex test tubes) in the following order: first, 1 ml of gelatin solution (1 % in 0.1 M phosphate buffer, pH 7.0), 50 μl of enzyme, one drop of starch solution (1 % soluble starch), 1 ml of Penicillin solution (Crystalline Sodium Penicillin G (Benzyl penicillin) IP, Alembic Ltd.) 1,660 μg mg<sup>−1</sup>, dissolved in 0.1 M phosphate buffer, pH 7.0, to contain not less than 5,000 μg ml<sup>−1</sup>), 3 ml of sample solution and finally, 2 ml of iodine (0.01 N iodine in 0.1 M potassium iodide) was added. Then the time of decolorization of iodine was recorded with a stopwatch; after addition of substrate (synthesized compounds), standard (Potassium Clavulanate) and blank was determined using water in place of sample solution.</p><sec id="Sec25"><title>Unit</title><p>Penicillinase activity is expressed in Pollock and Torriani unit. One unit is the amount of enzyme which will hydrolyze 1 μM Sodium Penicillin G in 1 h at pH 7.0 at 30 °C.</p></sec></sec><sec id="Sec26"><title>Antimicrobial screening</title><p>The antimicrobial assays were performed for synthesized compounds by cup-plate method of all the synthesized compounds, as antibacterial activity against <italic>S. aureus, B. subtilis, K. pneumoniae, E. coli, P. vulgaris, and S. typhi</italic> and antifungal activity against <italic>A. niger and C. albicans.</italic> This activity was expressed in terms of diameters of zone of inhibition in mm.</p></sec></sec></sec><sec id="Sec27" sec-type="conclusion"><title>Conclusion</title><p>In summary, a series of indolin-2-ones with <italic>N</italic>-diethyl amino and various thiosemicarbazide moiety were designed and synthesized. The cytotoxicity of all synthesized compounds was evaluated against two human cancer cell lines (CEM and HeLa) and murine leukemia cell line (L1210). Compound <bold>5c</bold> displayed an excellent cytotoxicity against all three cell lines tested; in particular, it showed potent cytotoxicity against CEM and L1210 cancer cell lines. The preliminary structure–activity relationship (SAR) studies revealed that combination of indolin-2-one core structure and 4-methoxy phenyl thiosemicarbazide moiety at the 3-position was more favorable. All the synthesized compounds were screened for cytotoxicity, β-lactamase inhibitory activity, antiviral, antibacterial, and antifungal activity against various strains of microorganisms. Derivative <bold>4b</bold>, <bold>5a</bold>, <bold>5b</bold>, and <bold>5d</bold> showed antiviral activity against HEL cell cultures in the range of 11–20 μM, in comparison with IC<sub>50</sub> values of 29, 10, >250, and >100 μM for standard brivudin, cidofovir, acyclovir, and ganciclovir, respectively. Mild to moderate antimicrobial activity was observed. 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